Thesis Abstract

<p> </p><p>The synthesis of five mono- and five bis-alkynylated derivatives of quinoline-5,8-diones is<br>reported. The intermediate 6,7-dibromoquinoline-5,8-dione was obtained by nitrosation of 8-<br>hydroxyquinoline, followed by reduction and subsequent bromination and oxidation. The coupling<br>reaction of 6,7-dibromoquinoline-5,8-dione via palladium-catalyzed Sonogashira cross-coupling<br>gave the alkynylated products. The chemical structures of the products were confirmed using<br>spectroscopic methods which include UV-visible spectrophotometry, Fourier Transform-Infrared<br>(FT-IR) spectroscopy, 1H and 13C-NMR spectroscopy. The antimicrobial properties of the<br>synthesized products were determined on Escherichia Coli 1, Escherichia Coli 12, Klebsiella<br>Pneumonia, Pseudomonas aeruoginosa and Staphylococcus aureus using the agar-diffusion<br>method. Results showed significant improvement in antibacterial activities compared with<br>ampicillin and gentamycin.</p><p>&nbsp;</p> <br><p></p>

Thesis Overview

<p> 1.0: INTRODUCTION<br>1.0: Background of Study<br>The chemistry of quinoline-5,8-dione as a functionality is a developing field because of its<br>various biological activities. Quinoline-5,8-dione 1, the parent functionality of a large number of<br>medicinal compounds have been of great interest to drug researchers due to its biological<br>functions as antifungal, antibacterial, antiparasitic and antitumor agents1. Streptonigrin and<br>Lavendamycin are known antibiotic, antitumor agents containing the quinoline-5,8-dione<br>functional group1<br>N<br>O<br>O<br>1<br>Since the discovery of the parent compound, many structural modifications have been<br>carried out in search of compounds with improved biological activities. Thus, subsequent<br>variations in the parent structure have given rise to a large number of derivatives of medicinal<br>interest. Substituted quinoline-5,8-diones are useful antifungicides and antibactericides whereas<br>some of the polynuclear quinones built on the dihaloquinoline quinine scaffold are useful<br>tuberculostatic and cytostatic substances2. A number of alkylene-imino quinones have been<br>prepared which are capable of inhibiting the growth of tumor nuclei3. Some hydroxyl and<br>amino-quinoline-quinones posses marked amoebicidal activity4.<br>2<br>Padwa’s group5 reported the synthesis of quinoline-5,8-dione analogues 2 and 3 using<br>two different methods. The first method used 7-aminoquinolinediones directly as coupling<br>partners to synthesize compound 2. The second method looked at synthesizing the quinoline-5,8-<br>dione after the cross coupling step to obtain compound 3. The synthesis is very similar to the<br>method Behforouz had published in 19971.<br>N<br>O<br>O<br>H2N Cl N<br>O<br>O<br>ACHN<br>N<br>CH3 3<br>2<br>The importance of the quinoline-5,8-dione prompted Behforouz1 to report the synthesis<br>of the analogue 4.<br>N CH3<br>O<br>O<br>H2N<br>4<br>Also in the year 1984, Kende and Ebetion6 reported the synthesis of lavendamycin methyl<br>ester 5, another analogue of quinoline-5,8-dione in a total of nine steps with an overall yield of<br>2%.<br>3<br>In 2010, Behforouz7, reported a study of the biological activities on the quinoline-5,8-diones<br>analogues 6. The compounds were synthesized through Pictet-Spendgler condensation of<br>quinolinedione aldehydes with trypophans.<br>HN<br>N<br>N<br>O<br>O<br>R1HN<br>R2<br>COR3<br>R4<br>R5<br>6<br>(R1 =CH3CO, CH3 (CH2)2, HCO, etc. R2 = H, Cl; R3 = OCH3, NH2, N[(CH2CH2)2]. R4 = H,<br>CH3. R5 = H, OH).<br>Padwa5 reported the synthesis of another new quinolinequinone derivative 7 from 8-hydroxytetra-<br>azole [1, 5-a] quinoline.<br>HN<br>N<br>N<br>O<br>O<br>CO2CH3 H2N<br>CH3<br>5<br>4<br>As a further variation in the structure of quinoline-5,8-dione in an effort to synthesize<br>new antifungal drugs, Chung12 synthesized new quinolinequinones with substitution at C-6 and<br>C-7 as represented as structures 8, 9, 10 and 11.<br>N<br>NH<br>X<br>O<br>O<br>R1<br>R2<br>R3 N<br>NH<br>SCH3<br>O<br>O<br>R1<br>R2<br>R3<br>N<br>NH<br>O<br>O<br>R1<br>R2<br>R3 SCN<br>N<br>O<br>O<br>X<br>S<br>R4<br>8 9<br>10<br>11<br>( R1 R2, R3 are the same or different and a halogen atom, or aceto group and R4 is C-1 to C-20<br>alkyl groups and X = a halogen atom8 ).<br>Among all the prepared quinolinequinones only 6,7-dichloro, 12 and 6,7-dibromo- 13<br>derivatives derived from the highly antibacterial 8-hydroxyquinoline 142 have been found to<br>possess antimicrobial activities comparable with those of 2,3-dichloro-1,4-naphthoquinoline 159.<br>N<br>O<br>O<br>Br N3<br>7<br>5<br>N<br>Cl<br>Cl<br>O<br>O<br>N<br>O<br>O<br>Br<br>Br N<br>OH<br>O<br>O<br>Cl<br>Cl<br>12 13 14<br>15<br>1.1: TANDEM CATALYSIS<br>The term tandem catalysis represents processes in which “the sequential transformation of<br>the substrate occurs via two (or more) mechanistically distinct processes”10. There are three types<br>of tandem catalysis namely:<br>(a) Orthogonal tandem catalysis: In this type of tandem catalysis, there are two or more<br>mechanistically distinct transformations, two or more functionally and ideally non-interfering<br>catalysts and all catalysts present from the outset of the reaction.<br>(b) Auto-tandem catalysis: Here, there are two or more mechanistically distinct transformations<br>which occur via a single catalyst precursor; both catalytic cycles occur spontaneously and there<br>is cooperative interaction of all species present at the outset of the reaction.<br>(c) Assisted tandem catalysis: In this type, two or more mechanistically distinct transformations<br>are promoted by a single catalytic species and the addition of a reagent is needed to trigger a<br>change in catalyst function10.<br>Transition metal catalyzed reactions are probably the most important area in organometallic<br>chemistry11. Interestingly, palladium catalyzed processes are the vastly applied process. It<br>typically utilizes only 1-5mol% of the catalyst12. The catalytic system is generally composed of a<br>6<br>metal and a ligand11. For most reactions, the active catalyst is the zerovalent metal, that is Pd(0)<br>and can be added as such, as a stable complex such as tetrakis(triphenylphosphine) Pd(PPh3)3<br>13.<br>On the other hand, a Pd(ll) pre-catalyst such as palladium acetate, together with a ligand (or<br>as a pre-formed catalyst) can be used and has the benefit of better stability for storage14. An<br>initial step, reduction of Pd(ll) to Pd(0), is required before the catalytic cycle can start15. This<br>reduction is usually brought about by a component of the reaction as shown below, but<br>sometimes separate reducing agents such as DIBAH can be used16.<br>PdX2 + Ph3P +H2O Pd(0)+ Ph3PO +2HX<br>X= halide. M= any metal, R= any type of organic moiety.<br>The ligand is the main variable in the catalyst system. Phosphines can be varied in steric<br>bulk or in their donor strength, increasing in the electron density on the metal and thus, the<br>reactivity of the catalyst to less reactive substrate such as chlorides. Steric bulk decreases the<br>number of ligands that can coordinate to the metal atom, thereby increasing its reactivity by<br>accelerating reductive elimination11.<br>1.2: Sonogashira Cross-coupling reaction<br>Carbon-carbon bond formation is a very important reaction in organic synthesis. The array<br>of transition-metal-catalyzed cross-coupling reactions can easily be considered nowadays<br>cornerstones in the field of organic synthesis17, 18, 19. Palladium-catalyzed Sonogashira crosscoupling20,<br>21 is one of the most powerful and straightforward methods for the formation of<br>carbon-carbon bonds in organic synthesis21, 22, 23. Other methods which have been used for the<br>same purpose includes Suzuki-Miyaura reaction, Stille reactions, Hiyama reactions, Negishi<br>7<br>reactions to mention but a few. Among them, the palladium-catalyzed Sonogashira sp2-sp<br>coupling reaction between aryl or alkenyl halides or triflates and terminal alkynes, with or<br>without the presence of a copper (1) cocatalyst, has become the most important method to<br>prepare arylalkynes and conjugated enynes, which are precursors for natural products,<br>pharmaceuticals, and molecular organic materials22, 24. Traditionally, these cross-coupling<br>reaction rely on the presence of both palladium and copper to contribute to catalysis25, although<br>much effort of late has gone into effecting such C-C bond constructions in the absence of one21,26<br>or the other metal21, 27 or by virtue of alternative methodologies that accomplish the same net<br>aryl-alkynes bond 21, 28.<br>1.3: STATEMENT OF PROBLEM<br>Though there are various alkylated derivatives of quinoline-5,8-diones with reported<br>biological properties, the synthesis of its alkynylated derivatives is yet unknown. In fact, no<br>significant work has been reported on using the Sonogashira cross-coupling reaction to extend<br>the conjugation of halogenated quinoline-5,8-diones. It is the interest in these type of<br>compounds and their medicinal value that informs the quest for the synthesis of new mono-and<br>bis-alkynylated quinoline-5,8-diones.<br>1.4: Objectives of Study.<br>The objectives of this work therefore were to:<br>1. Synthesize functional halogenated quinoline-5,8-dione intermediates of the structure 13:<br>8<br>N<br>O<br>O<br>Br<br>Br<br>13<br>2. Convert the halogenated quinoline-5,8-dione (13) to the relevant derivatives (131E1-5) and<br>(132E1-5) respectively via palladium-catalyzed Sonogashira cross-coupling reaction under<br>copper-, amine-, and solvent-free conditions. (Schemes 3 and 4 where R1= aryl, alkyl, alkoxy,<br>etc.)<br>N<br>O<br>O<br>Br<br>Br<br>+ R CH 1<br>3 mol%,PdCl2(PPh3)2<br>TBAF,800C,N2 N<br>O<br>O<br>R1<br>Br<br>13 (131E1-5)<br>Scheme 1: Palladium-catalyzed Sonogashira synthesis of mono-alkynylated quinoline-5,8-diones<br>under copper-, amine-, and solvent-free Conditions.<br>N<br>O<br>O<br>Br<br>Br<br>+ R CH 1<br>3 mol%,PdCl2(PPh3)2<br>TBAF,800C,N2 N<br>O<br>O<br>R1<br>R1<br>2<br>13 (132E1-5)<br>9<br>Scheme 2: Palladium-catalyzed Sonogashira synthesis of bis-alkynylated quinoline-5,8-diones<br>under copper-, amine-, and solvent-free Conditions.<br>3. Characterize the mono- and bis-alkynylated derivatives of quinoline-5,8-diones (131E1-5) and<br>(132E1-5) respectively, with Uv-visible, IR, 1H-NMR and 13C-NMR spectroscopy<br>4. Evaluate the antimicrobial activities of the new alkynylated quinoline-5,8-diones.<br>1.5: Justification of the Study<br>The wide therapeutic applications of quinoline-5,8-diones derivatives and unavailability of<br>its alkynylated derivatives in the literature necessitates this research. <br></p>